The postmarketing safety record of two recently approved dru gs with novel mechanisms of action has raised concerns, leading investigators to examine how these agents got approved in the first place, according to a report by the Institute for Safe Medication Practices (ISMP).

The FDA approved pimavanserin in April 2016 for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Approximately 50% of patients with Parkinson’s will develop hallucinations and other forms of psychosis as the disease progresses, according to the ISMP report. This often is caused by the medications commonly used to treat Parkinson’s, namely, levodopa—typically given in combination with carbidopa—and dopamine agonists (e.g., pramipexole).

Although most antipsychotic drugs primarily block normal signaling of the neurotransmitter dopamine, “pimavanserin acts to block signaling with an important subfamily of serotonin receptors (5 HT2A) that mediate memory, cognition, learning and numerous other body functions,” the report noted. Pimavanserin initially was indicated for a very specific side effect of Parkinson’s, but the drug now is “being tested for use in larger patient populations, including those with psychosis in Alzheimer’s, and as adjunct therapy in schizophrenia,” the ISMP report stated.

In the 12 months ending March 2017, 2,236 AEs were reported to the FDA Adverse Event Reporting System related to pimavanserin. The ISMP team looked at the most frequently reported AEs and divided them into four groups: hallucinations (21.8%), drug ineffective (14.9%), confusion (11.5%) and death (10.9%). Further analysis provided additional evidence that AE reports of hallucinations likely were showing that the drug was making psychosis worse or was ineffective in some patients. “The number of reports of hallucinations was large [n=487], with 73% observed by health professionals, who could be expected to understand that hallucinations occur in 20% to 70% of Parkinson’s patients,” ISMP noted.

A Scary Picture

The most frequently reported adverse events related to pimavanserin:

Hallucinations (21.8%)

Drug ineffective (14.9%)

Confusion (11.5%)

Death (10.9%)

Source: FDA Adverse Event Reporting System.

The AE data mirrored results of the clinical trial of pimavanserin. In that study, “both hallucinations and confusional state also occurred more frequently as an adverse event in treated patients compared with those getting a placebo,” according to ISMP. A closer look at the FDA approval process revealed that pimavanserin was approved based on limited scientific evidence, the group noted. “[The approval] relied on a single clinical trial indicating a minimal treatment effect, used a measurement scale for symptoms that had not been validated, and succeeded only after three previous trials had failed to demonstrate a benefit,” ISMP noted. “Further, the agency’s medical reviewer recommended against approval and was overruled.” According to ISMP, the reviewer “noted that although other psychiatric drugs were often approved on limited evidence of benefit, in the case of pimavanserin, [the] treatment more than doubled the risk of death and/or serious adverse events in its pivotal trial.”

ISMP found that the post-approval AE reports disclosed an additional safety issue: “We identified 318 cases where pimavanserin was combined with quetiapine (Seroquel [AstraZeneca]) or other antipsychotics that block dopamine signaling. These drugs are not recommended for use in the elderly and are not approved for use in Parkinson’s.”

ISMP noted that it shared its preliminary results with the manufacturer, ACADIA. The company responded by claiming that the large volume of AEs attributed to its drug were due in part “to the manufacturer’s extensive contact with health professionals and consumers through a specialty pharmacy network that distributed the drug, and because of a company patient support program,” the ISMP report stated. “[ACADIA] also said the reports of hallucinations might have occurred before the drug became fully effective approximately four weeks after treatment started.”

ISMP took issue with at least some of that reasoning. “While the company’s contacts with health professionals and consumers likely expanded the number of adverse event reports after product launch, these reports nevertheless reflect the experiences of health professionals and consumers in a real-life, post-market setting … [where] hundreds of health professionals are trying this new drug with their patients and reporting that either it is not providing the expected benefit or [is] making some psychosis worse.”

ISMP urged the FDA and ACADIA to “consider additional warnings and other measures to deal with inappropriate combination therapy with antipsychotic drugs” such as pimavanserin.

Sacubitril-Valsartan Signals

Sacubitril-valsartan was approved in July 2015. The agent targets a new pathway involved in the regulation of blood pressure and “appears to improve mortality and cardiovascular outcomes in heart failure patients with reduced ejection fraction,” according to the ISMP QuarterWatch report.

Like pimavanserin, the combination therapy was approved with evidence from a single trial, in this case a 27-month trial involving 8,442 patients. The trial was stopped early because of reduced cardiovascular mortality: from 16.5% among patients taking enalapril to 13.3% among those taking the combination agent. However, according to ISMP, “only patients with the best chance of benefiting from the drug were selected for the trial after a six-week run-in period to ensure tolerance to the drug and eliminate those experiencing early adverse drug effects.”

In that study, 24.4% of patients experienced a hypotension-related AE, which FDA reviewers noted was likely an underestimate, given that the trial was conducted only with patients already known to tolerate the drug without AEs serious enough to warrant discontinuation.

When reviewing the AE data, ISMP found that hypotension was the leading AE reported for sacubitril-valsartan during the 12 months ending in March 2017, with symptoms ranging from dizziness to blackouts. “We identified 1,684 [AEs] indicating a hypotension-related event, more than with any other cardiovascular drug in this period,” ISMP reported. Morbidity associated with the AEs, which occurred in older patients (median age, 70 years), was “not severe in two-thirds of the cases,” but 69 deaths were reported. “The patient population taking this drug is substantial, with prescription growth increasing an average of 38% per quarter,” the report noted.

“While Entresto had consistently positive results in its one large clinical trial, the adverse event data illustrate the importance of clinicians being alert to the risks of hypotension,” ISMP stated, recommending that the “FDA and the manufacturer review existing safety data to see what additional warnings and precautions, such as more gradual escalation of the dose to the recommended level, might help reduce the risk of this adverse effect.”